X-linked lymphoproliferative disease type 1 (XLP1) is a rare primary immunodeficiency caused by pathogenic variants in the SH2D1A gene, characterized by a dysregulated immune response to Epstein–Barr virus (EBV), hypogammaglobulinemia, a markedly increased risk of hemophagocytic lymphohistiocytosis (HLH) and EBV-driven lymphoproliferation, while Hodgkin lymphoma (HL) represents an exceptionally rare complication.
We report a male patient diagnosed with XLP1 at the age of six following his first episode of HLH, with confirmation of a pathogenic SH2D1A variant. Cytogenetic analysis revealed a 47, XYY karyotype. The patient remained clinically stable until the age of 28, when he experienced a new episode of EBV reactivation-associated HLH. Treatment with dexamethasone and immunomodulatory doses of intravenous immunoglobulin (IVIG) resulted in prompt clinical improvement, and a long-term IVIG replacement was initiated due to hypogammaglobulinemia. Four months later, the patient presented with severe abdominal pain, fever, pancytopenia, splenomegaly, hyperferritinemia, and markedly elevated soluble IL-2 receptor levels (9,840 IU/mL), consistent with a third episode of EBV-associated HLH (viral load 207,000 viral copies/mL). Treatment was initiated according to the HLH-2014 protocol, including dexamethasone, immunomodulatory IVIG, and rituximab. Despite transient improvement, clinical and laboratory deterioration occurred, prompting escalation with high-dose methylprednisolone pulses, leading to significant clinical improvement. Interestingly, bone marrow biopsy performed before treatment revealed infiltration consistent with HL. Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) demonstrated active disease in the spleen and bone marrow, establishing a stage IVA diagnosis. Chemotherapy with the ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) protocol was initiated. After two cycles, interim FDG-PET/CT showed complete metabolic remission (Deauville score 1/2), and treatment continued with four cycles of AVD, according to European Society for Medical Oncology (ESMO) guidelines.
This case illustrates that XLP1 patients remain at lifelong risk for EBV-driven HLH and rare lymphomas, and emphasizes that early recognition, vigilant monitoring, and prompt targeted therapy, including rituximab and tailored chemotherapy, can achieve complete remission, even in this high-risk population.
